Project Summary Auditory perceptual learning induces plasticity in the auditory cortex (A1) that can improve hearing perception, but the neural mechanisms that trigger these changes are unclear. Across sensory cortical regions, inhibitory interneurons are emerging as ?gate keepers? to plasticity - regulating tightly controlled balances between excitation and inhibition. The cortical interneuron population is composed of numerous cell subtypes distinguished by morphology, physiology, and connectivity, suggesting that there are several distinct circuits for plasticity regulation. How these specific interneuron circuits contribute to cortical plasticity and sensory learning remains poorly understood. Recent work suggests that inhibitory interneurons within the superficial layers of A1 promote auditory plasticity. These interneurons are characterized by expression of the serotonin receptor, 5HT3A-R, and are responsive to acetylcholine. While multiple studies have focused on the role of acetylcholine signaling in A1 plasticity, little is known about the function of serotonin. This proposal focuses on a subset of superficial 5HT3A-R interneurons expressing vasoactive intestinal peptide (VIP) that are a promising target for regulating plasticity in adult A1. The studies will test the hypothesis that serotonin signaling to VIP interneurons promotes plasticity in mouse A1 during auditory perceptual learning. First, circuit tracing techniques will be used to identify the serotonin- expressing neurons that synapse onto VIP interneurons in A1. Second, in vivo two-photon imaging will determine when serotonergic terminals and VIP interneurons in A1 are recruited during sound discrimination learning. These studies will 1) identify a previously uncharacterized serotonin neuron to VIP interneuron circuit, and 2) will determine whether changes in serotonin signaling to VIP interneurons underlie A1 plasticity during auditory perceptual learning. The results of this research will likely open new horizons for the discovery of novel therapies that tap into specific cortical circuits to promote adult plasticity.